The Radiation Therapy Oncology Group (RTOG) is the leading multicenter and multidisciplinary research organization systematically testing novel radiotherapy (RT) approaches against cancer and pursuing fully integrated translational research to enhance this effort. The group will build on its outstanding scientific accomplishments in the current funding period to conduct research based on three fundamental initiatives: 1. Physical Targeting: RTOG will implement and test advances in imaging and high-precision RT planning and delivery technologies in clinical trials. 2. Molecular Targeting: Combined with RT: RTOG will design and conduct hypothesis-driven trials testing the integration of novel molecular targeted anti-cancer agents with optimized RT or chemo-RT. 3. Translational Research: RTOG will implement powerful biostatistical and medical informatics approaches to its unique and inter-linked clinical, biophysical, biologic, and outcomes databases that will faciliate hypothesis-driven analyses of these resources. The RTOG's research is primarily directed toward patients with brain tumors, head and neck cancer, lung cancer, gastrointestinal cancer, and genitourinal cancer. More limited research strategies have been developed for patients with gynecologic and breast cancer and sarcoma. RTOG research is supported by outstanding contributions from the Advanced Technology Integration, the Translational Research Program, and the Health Services Research and Outcomes Committees as well as the newly relocated Biospecimen Resource and from the four core committees of Medical Oncology, Medical Physics, Pathology, and Surgical Oncology. These contributions are well coordinated by a strong administrative and scientific infrastructure and have resulted in increased productivity in the current as compared with the prior funding cycle in terms of: 1. publication record;2. clinical trials activated and completed;3. overall patient accrual;4. public and private funding of group research;5. collaboration with other cooperative groups and other NIH-funded organizations;and 6. increased participation and leadership of Canadian investigators, with 8 of 37 full member institutions being Canadian. Close to two-thirds of all cancer patients receive radiation therapy for cure or for symptom relief. Novel technology, molecular targeted drugs and advances in radiation and cancer biology will improve the success rate of radiation therapy through clinical research over the next six years.